Infection with human immunodeficiency virus (HIV) leads to the devastating loss of CD4+ T cells and progression to acquired immunodeficiency syndrome (AIDS). As of 2010, roughly 33.3 million people were living with HIV/AIDS worldwide (44, 49), and despite the advent of anti-retroviral therapy, HIV infection is still considered a global pandemic. An effective vaccine or cure for HIV infection remains elusive in part because basic principles of how HIV is sensed by the immune system are not completely clear. Clues for how HIV infection could be curtailed can be found in a population of HIV-infected individuals termed 'elite controllers', that are able to maintain plasma levels of virions to less than 50 copis per ml and do not progress to AIDS. These rare individuals exhibit a remarkable ability to 'control' viral infection and compared to other infected individuals they display a qualitatively different CD8+ T cell response, which may be critical for host control of viremia. With this projec we seek to elucidate pathways of HIV-mediated activation of immune responses in dendritic cells (DCs), professional antigen presenting cells that link innate detection of microorganisms to cellular and adaptive immune responses. Our laboratory has recently shown the existence of an interferon regulatory factor 3 (IRF3)-dependent innate response to HIV in DCs (24), but this response is cryptic since HIV does not typically infect DCs. For this project we will study pathways of innate immune signaling in DCs and evaluate how cellular components can 'sense' viral infection. To this end we propose the following aims: 1) explore how HIV-1 influences an innate response in DCs through the IRF3 pathway; and 2) examine whether innate activation and cytokine production in DCs is fundamentally different in HIV-infected elite controllers. Ultimately, we hope to recapitulate what processes may be at play in elite controllers and improve our understanding of HIV pathogenesis.